This application claims priority of Danish application serial no. 1089/96 filed Oct. 4, 1996, the contents of which are fully incorporated herein by reference.
The present invention relates to novel N-substituted azaheterocyclic compounds in which a substituted alkyl chain forms part of the N-substituent or salts thereof, to methods for their preparation, to compositions containing them, to the use of the compounds for preparing compositions for the clinical treatment of painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role by eliciting neurogenic pain or inflammation, and to methods of treating said painful, hyperalgesic and/or inflammatory conditions. The invention also relates to the use of the present compounds for reducing blood glucose and/or inhibit the secretion, circulation or effect of insulin antagonising peptides like CGRP or amylin, the present compounds being known to interfere with neuropeptide containing C-fibres. Hence the present compounds can be used in the treatment of insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM) in order to improve the glucose tolerance as well as ageing-associated obesity.
The nervous system exerts a profound effect on the inflammatory response. Antidromic stimulation of sensory nerves results in localised vasodilation and increased vascular permeability (Janecso et al. Br. J. Pharmacol. 1967, 31, 138-151) and a similar response is observed following injection of peptides known to be present in sensory nerves. From this and other data it is postulated that peptides released from sensory nerve endings mediate many inflammatory responses in tissues like skin, joint, urinary tract, eye, meninges, gastrointestinal and respiratory tracts. Hence inhibition of sensory nerve peptide release and/or activity, may be useful in treatment of, for example arthritis, dermatitis, rhinitis, asthma, cystitis, gingivitis, thrombo-phlelitis, glaucoma, gastrointestinal diseases or migraine.
Further, the potent effects of CGRP on skeletal muscle glycogen synthase activity and muscle glucose metabolism, together with the notion that this peptide is released from the neuromuscular junction by nerve excitation, suggest that CGRP may play a physiological role in skeletal muscle glucose metabolism by directing the phosphorylated glucose away from glycogen storage and into the glycolytic and oxidative pathways (Rossetti et al. Am. J. Physiol. 264, E1-E10, 1993). This peptide may represent an important physiological modulator of intracellular glucose trafficking in physiological conditions, such as exercise, and may also contribute to the decreased insulin action and skeletal muscle glycogen synthase in pathophysiological conditions like NIDDM or ageing-associated obesity (Melnyk et al. Obesity Res. 3, 337-344, 1995) where circulating plasma levels of CGRP are markedly increased. Hence inhibition of release and/or activity of the neuropeptide CGRP may be useful in the treatment of insulin resistance related to type 2 diabetes or ageing.
In U.S. Pat. No. 4,383,999 and U.S. Pat. No. 4,514,414 and in EP 236342 as well as in EP 231996 some derivatives of N-(4,4-disubstituted-3-butenyl)azaheterocyclic carboxylic acids are claimed as inhibitors of GABA uptake. In EP 342635 and EP 374801, N-substituted azaheterocyclic carboxylic acids in which an oxime ether group and vinyl ether group forms part of the N-substituent respectively are claimed as inhibitors of GABA uptake. Further, in WO 9107389 and WO 9220658, N-substituted azacyclic carboxylic acids are claimed as GABA uptake inhibitors. EP 221572 claims that 1-aryloxyalkylpyridine-3-carboxylic acids are inhibitors of GABA uptake.
WO 9518793 discloses N-substituted azaheterocyclic compounds in which an unsubstituted alkyl chain containing from 2 to 4 carbon atoms forms part of the N-substituent.
The present invention relates to compounds of the general formula I, wherein X, Y, Z, M1, M2, R1 through R20, r, s, n, m and p are as defined in the detailed part of the present description.
The present compounds are useful for the treatment, prevention, elimination, alleviation or amelioration of an indication related to all painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role, e.g. neurogenic pain, inflammation, migraine, neuropathy, itching and rheumatoid arthritis, as well as indications caused by or related to the secretion and circulation of insulin antagonising peptides, e.g. non-insulin-dependent diabetes mellitus (NIDDM) and ageing-associated obesity.
In another aspect, the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of the general formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
In another aspect of the present invention there is provided a method of treating painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role, e.g. neurogenic pain, inflammation, migraine, neuropathy, itching and rheumatoid arthritis, as well as a method of treating indications caused by or related to the secretion and circulation of insulin antagonising peptides like CGRP or amylin, e.g. non-insulin-dependent diabetes mellitus (NIDDM) and ageing-associated obesity. The method of treating may be described as the treatment of one of the above indications in a subject in need thereof, which comprises the step of administering to the said subject a neurologically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.
A further aspect of the invention relates to the use of a compound of the present invention for the preparation of a pharmaceutical composition for the treatment of all painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role, e.g. neurogenic pain, inflammation, migraine, neuropathy, itching and rheumatoid arthritis, as well as for the treatment of indications caused by or related to the secretion and circulation of insulin antagonising peptides, e.g. non-insulin-dependent diabetes mellitus (NIDDM) and ageing-associated obesity.
Further objects will become apparent from the following description.
Accordingly, the present invention relates to novel N-substituted azaheterocyclic compounds of formula I 
wherein R1 and R2 independently are hydrogen, halogen, trifluoromethyl, hydroxy, C1-6-alkyl or C1-6-alkoxy; and
X is ortho-phenylene, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94C(R3R4)xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94(Cxe2x95x90O)xe2x80x94, xe2x80x94(Cxe2x95x90O)xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94N(R5)xe2x80x94(Cxe2x95x90O)xe2x80x94, xe2x80x94(Cxe2x95x90O)xe2x80x94N(R5)xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94(CH2)N(R5)xe2x80x94, xe2x80x94N(R5)(CH2)xe2x80x94, xe2x80x94N(CH3)SO2xe2x80x94, xe2x80x94SO2N(CH3)xe2x80x94, xe2x80x94CH(R6)CH2xe2x80x94, xe2x80x94CH2CH(R6)xe2x80x94, xe2x80x94(Cxe2x95x90O)xe2x80x94, xe2x80x94(R7)xe2x80x94 or xe2x80x94(Sxe2x95x90O)xe2x80x94 wherein R3, R4, R5 and R7 independently are hydrogen or C1-6-alkyl; and wherein R6 is C1-6-alkyl or phenyl; and
Y is  greater than Nxe2x80x94,  greater than CHxe2x80x94,  greater than Nxe2x80x94(Cxe2x95x90O)xe2x80x94 or  greater than Cxe2x95x90C(R8)xe2x80x94, wherein only the underscored atom participates in the ring system and wherein R8 is hydrogen or C1-6-alkyl; and
A is xe2x80x94CHxe2x95x90CR9xe2x80x94, xe2x80x94CR9xe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94(Cxe2x95x90O)xe2x80x94, xe2x80x94(Cxe2x95x90CH2)xe2x80x94, xe2x80x94(CR9R10)xe2x80x94, xe2x80x94CH(OR11)xe2x80x94, xe2x80x94CH(NHR11)xe2x80x94, phenylene, C3-7-cycloalkylene or the completion of a bond wherein R9 and R10 independently are hydrogen, C1-6-unbranched alkyl, C3-6-branched alkyl or C3-7-cycloalkyl and wherein R11 is hydrogen or C1-6 alkyl; and
r and s independently are 0, 1, 2, 3 or 4; and
Z is selected from 
xe2x80x83wherein n is 0, 1 or 2; and
R11 is hydrogen, C1-6-alkyl, C1-6-alkoxy or phenyl optionally substituted with halogen, triflouromethyl, hydroxy, C1-6-alkyl or C1-6-alkoxy; and
R12 is xe2x80x94(CH2)mOH or xe2x80x94(CH2)pCOR17 wherein m is 0, 1, 2, 3, 4, 5 or 6 and p is 0 or 1; and wherein R17 is xe2x80x94OH, xe2x80x94NHR20 or C1-6-alkoxy, wherein R20 is hydrogen or C1-6-alkyl; and
R13 is hydrogen, halogen, trifluoromethyl, hydroxy, C1-6-alkyl or C1-6-alkoxy; and
R14 is hydrogen or C1-6-alkyl; and
B is C1-6-alkylene, C2-6-alkenylene or C2-6-alkynylene; and
..... is optionally a single bond or a double bond; and
R18 is selected from 
xe2x80x83wherein M1 and M2 independently are C or N; and
R19 is hydrogen, C1-6-alkyl, phenyl or benzyl; and
R15 is hydrogen, halogen, trifluoromethyl, nitro or cyano; and
R16 is hydrogen, halogen, trifluoromethyl, nitro, cyano, xe2x80x94(CH2)mCOR17, xe2x80x94(CH2)mOH or xe2x80x94(CH2)mSO2R17, wherein m is 0, 1 or 2; or
R16 is selected from 
or a pharmaceutically acceptable salt thereof.
Compounds of formula I wherein Y is  greater than Cxe2x95x90CHxe2x80x94, A is xe2x80x94CH2xe2x80x94 and r+sxe2x89xa62, or
Y is  greater than Cxe2x95x90CHxe2x80x94, A is the completion of a bond and r+sxe2x89xa63, or
Y is  greater than Nxe2x80x94 or  greater than CHxe2x80x94, A is xe2x80x94CH2xe2x80x94 and r+sxe2x89xa63, or
Y is  greater than Nxe2x80x94 or  greater than CHxe2x80x94, A is the completion of a bond and r+sxe2x89xa64, and
Z is selected from 
xe2x80x83wherein R17 is xe2x80x94OH or C1-6-alkoxy, are known from WO 9518793.
The compounds of formula I may exist as geometric and optical isomers and all isomers, as separated, pure or partially purified stereoisomers or racemic mixtures thereof are included in the scope of the invention. Isomers may be separated by means of standard methods such as chromatographic techniques or fractional crystallisation of suitable salts.
Preferably, the compounds of formula I exist as the individual geometric or optical isomers.
The compounds according to the invention may optionally exist as pharmaceutically acceptable acid addition salts orxe2x80x94when the carboxylic acid group is not esterifiedxe2x80x94as pharmaceutically acceptable metal salts orxe2x80x94optionally alkylatedxe2x80x94ammonium salts.
Examples of such salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate or similar pharmaceutically acceptable inorganic or organic acid addition salts, and include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) which are known to the skilled artisan.
Also included are the hydrates of the above mentioned acid addition salts which the present compounds are able to form.
The acid addition salts may be obtained as the direct products of compound synthesis. In the alternative, the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or by precipitation or crystallisation.
The compounds of formula I may be administered in a pharmaceutically acceptable acid addition salt form or where possible as a metal or a lower alkylammonium salt. Such salt forms exhibit approximately the same order of activity as the free base forms.
In the above structural formula and throughout the present specification, the following terms have the indicated meaning:
The term xe2x80x9cC1-6-alkylxe2x80x9d as used herein, alone or in combination, refers to a straight or branched, saturated hydrocarbon chain having 1 to 6 carbon atoms such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 4-methylpentyl, neopentyl, n-hexyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and 1,2,2-trimethylpropyl.
The term xe2x80x9cC1-6-alkoxyxe2x80x9d as used herein, alone or in combination, refers to a straight or branched monovalent substituent comprising a C1-6-alkyl group linked through an ether oxygen having its free valence bond from the ether oxygen and having 1 to 6 carbon atoms e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy.
The term xe2x80x9chalogenxe2x80x9d means fluorine, chlorine, bromine or iodine.
In a preferred embodiment of the invention R1 and R2 are selected from hydrogen halogen, trifluoromethyl or C1-6-alkyl. Preferably R1 and R2 are hydrogen, chloro or methyl.
In a another preferred embodiment of the invention X is selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94OCH2Oxe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94Sxe2x80x94. Preferably X is xe2x80x94CH2CH2xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94Oxe2x80x94.
In another preferred embodiment of the invention Y is selected from  greater than Nxe2x80x94,  greater than CHxe2x80x94,  greater than Nxe2x80x94 (Cxe2x95x90O)xe2x80x94 or  greater than Cxe2x95x90C(R8)xe2x80x94, wherein only the underscored atom participates in the ring system and wherein R8 is hydrogen or methyl.
In another preferred embodiment of the invention A is selected from xe2x80x94CHxe2x95x90CR9xe2x80x94, xe2x80x94CR9xe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94(Cxe2x95x90O)xe2x80x94, xe2x80x94(CR9R10)xe2x80x94, xe2x80x94CH(OR11)xe2x80x94, phenylene or the completion of a bond, wherein R9 and R10 independently are hydrogen, C1-6-unbranched alkyl, and wherein R11 is hydrogen or C1-6 alkyl.
In another preferred embodiment of the invention r is 0, 1 or 2.
In another preferred embodiment of the invention s is 0, 1 or 2.
In another preferred embodiment of the invention Z is selected from 
wherein R12, R13 and R18 are as defined above.
In another preferred embodiment of the invention R12 is xe2x80x94(CH2)pCOR17 wherein p is 0 or 1 and R17 is xe2x80x94OH.
In another preferred embodiment of the invention R18 is 
wherein M1 and M2, R15 and R16 are as defined above.
In yet another preferred embodiment of the invention R16 is (CH2)mCOR17 wherein m is 0 or 1 and R17 is xe2x80x94OH.
Preferred compounds of the present invention include:
1-(3-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)-(2R)-methyl-1-propyl)-(3R)-piperidinecarboxylic acid;
1-(3-(10,11-Dihydro-5H-dibenzo[b,d]azepin-5-yl)-(2R)-methyl-1-propyl)-4-piperidinecarboxylic acid;
1-(3-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)-(2R)-methyl-1-propyl)-(2R)-piperidinecarboxylic acid;
1-(4-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)-(2Z)-butenyl)-(3R)-piperidinecarboxylic acid;
1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propionyl)-(3R)-piperidinecarboxylic acid;
1-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-1-ethyl)-(3R)-piperidinecarboxylic acid;
1-(4-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)-(2E)-butenyl)-(3R)-piperidinecarboxylic acid;
1-(2-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-methyl-1-ethyl)-(3R)-piperidinecarboxylic acid;
1-(3-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)-2-methyl-3-oxopropyl)-(3R)-piperidinecarboxylic acid;
1-(4-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)-2-butynyl)-(3R)-piperidinecarboxylic acid;
1-(3-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-methyl-1-propyl)-(3R)-piperidinecarboxylic acid;
1-(3-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)-2-hydroxy-1-propyl)-(3R)-piperidinecarboxylic acid;
1-(2-(10,11-Dihydro-dibenzo[b,f]azepin-5-ylmethyl)-1-pentyl)-(3R)-piperidinecarboxylic acid;
1-(3-(3-Chloro-10,11-dihydro-5H-dibenzo[b,d]azepin-5-yl)-(2R)-methyl-1-propyl)-(3-piperidinecarboxylic acid;
1-(3-(3-Trifluoromethyl-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-(2R)-methyl-1-propyl)-(3R)-piperidinecarboxylic acid;
1-(3-(3-Methyl-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-(2R)-methyl-1-propyl)-(3R)-piperidinecarboxylic acid;
1-(3-(3-Methoxy-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-(2R)-methyl-1-propyl)-(3R)-piperidinecarboxylic acid;
1-(3-(2-Chloro-10,11-dihydro-5H-dibenzo[b,d]azepin-5-yl)-(2R)-methyl-1-propyl)-(3R)-piperidinecarboxylic acid;
2-(4-(3-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)-(2R)-methyl-1-propyl)-1-piperazinyl)-nicotinic acid;
1-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-(3R)-piperidinecarboxylic acid;
1-(2-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)-cyclopropylmethyl)-(3R)-piperidinecarboxylic acid;
1-(2-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)-cyclopentylmethyl)-(3R)-piperidinecarboxylic acid;
1-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-1-ethyl)-(3R)-piperidinecarboxylic acid;
(R)-1-(3-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)-3-oxopropyl)-3-piperidinecarboxylic acid;
(R)-1-(4-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-benzyl)-3-piperidinecarboxylic acid;
(R)-1-(4-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)-2-butyn-1-yl)-3-piperidinecarboxylic acid;
(R)-1-((2R)-Methyl-3-(3-methyl-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-propyl)-4-piperidinecarboxylic acid;
(R)-1-(3-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)1-methylpropyl)-3-piperidinecarboxylic acid;
(R)-1-(2-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-methyl-ethyl)-3-piperidinecarboxylic acid;
(R)-1-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3-piperidinecarboxylic acid;
(R)-1-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methyl)-3-piperidinecarboxylic acid;
1-(3-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)-(2R)-methyl-1-propyl)-3-pyrrolidinylacetic acid:
2-(1-(3-(10,11-Dihydrodibenzo[b,f]azepin-5-yl)-(2R)-methylpropyl)-4-piperazinyl)-nicotinic acid;
(R)-1-(2-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-ylmethyl)-1-pentyl)-3-piperidinecarboxylic acid;
2-(4-(3-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)-2-hydroxypropyl)piperazin-1-yl)nicotinic acid;
1-(3-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)-2-methyl-3-oxo-propyl)-3-piperidinearboxylic acid;
(R)-1-(3-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-propionyl)-3-piperidinecarboxylic acid;
1-(3-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-propionyl)-4-piperidinecarboxylic acid;
(R)-1-(2-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-ylcarbonyl)-1-benzyl)-3-piperidinecarboxylic acid;
(R)-1-(2-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-ylmethyl)-benzyl)-3-piperidinecarboxylic acid;
(R)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-3-oxo-1-propyl)-3-piperidinecarboxylic acid;
1-(3-(3-Chloro-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-(2R)-methylpropyl)-4-piperidine carboxylic acid;
(3-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)-2-hydroxy-propyl)-4-piperidinecarboxylic acid;
(R)-1-(3-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)-2-hydroxypropyl)-3-piperidinecarboxylic acid;
1-(3-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)-2-propoxypropyl)-4-piperidinecarboxylic acid;
(R)-1-(2-(N-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-N-methylamino)ethyl)-3-piperidinecarboxylic acid;
or a pharmaceutically acceptable salt thereof.
It has been demonstrated that the novel compounds of formula I inhibit neurogenic inflammation which involves the release of neuropeptides from peripheral and central endings of sensory C-fibres. Experimentally this can be demonstrated in animal models of histamine induced paw oedema (Amann et al, Europ. J. Pharmacol. 279, 227-231, 1995) in which the novel compounds of formula I exhibit a potent inhibitory effect. Compounds of formula I may be used to treat all painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role by eliciting neurogenic pain or inflammation, i.e.:
Acutely painful conditions exemplified by migraine, postoperative pain, burns, bruises, post-herpetic pain (Zoster) and pain as it is generally associated with acute inflammation; chronic, painful and/or inflammatory conditions exemplified by various types of neuropathy (diabetic, post-traumatic, toxic), neuralgia, rheumatoid arthritis, spondylitis, gout, inflammatory bowel disease, prostatitis, cancer pain, chronic headache, coughing, asthma, itching, chronic pancreatitis, inflammatory skin disease including psoriasis and autoimmune dermatoses, osteoporotic pain.
Further, it has been demonstrated that the compounds of general formula I improve the glucose tolerance in diabetic ob/ob mice and that this may result from the reduced release of CGRP from peripheral nervous endings. Hence the compounds of general formula I may be used in the treatment of NIDDM as well as ageing-associated obesity. Experimentally this has been demonstrated by the subcutaneous administration of glucose into ob/ob mice with or without previous oral treatment with a compound of general formula I.
The compounds of formula I may be prepared by the following method: 
A compound of formula II wherein R1, R2, X, Y, A, r and s are as defined above and W is a suitable leaving group such as halogen, p-toluene sulphonate or mesylate may be reacted with an aza compound of formula III wherein Z is as defined above. This alkylation reaction may be carried out in a solvent such as acetone, dibutylether, 2-butanone, methyl ethyl ketone, ethyl acetate, tetrahydrofuran (THF) or toluene in the presence of a base e.g. sodium hydride or potassium carbonate and a catalyst, e.g. an alkali metal iodide at a temperature up to reflux temperature for the solvent used for e.g. 1 to 120 h. If esters have been prepared in which R17 is alkoxy, compounds of formula I wherein R17 is OH may be prepared by hydrolysis of the ester group, preferably at room temperature in a mixture of an aqueous alkali metal hydroxide solution and an alcohol such as methanol or ethanol, for example, for about 0.5 to 6 h.
Compounds of formula II and III may readily be prepared by methods familiar to those skilled in the art.
Under certain circumstances it may be necessary to protect the intermediates used in the above methods e.g. a compound of formula III with suitable protecting groups. The carboxylic acid group can, for example, be esterified. Introduction and removal of such groups is described in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d J. F. W. McOrnie ed. (New York, 1973).
The rat histamine paw oedema test was performed essentially as described by Amann et al. (Europ. J. Pharmacol. 279, 227-231, 1995). In brief 250-300 g male Sprague-Dawley rats were anaesthetized with pentobarbital sodium, and placed on a 32 degree (Celsius) heated table. Ten minutes later histamine (50 micoliter, 3 mg/ml) was injected in the right hind paw and 20 minutes hereafter the paw swelling was determined by water plethysmography (Ugo Basile). Test compounds were administered intraperitoneally at 15 minutes before the anaesthetics.
ob/ob female mice, 16 weeks of age, where injected glucose (2 g/kg) subcutaneously. At times hereafter blood glucose was determined in tail venous blood by the glucose oxidase method. At the end of the study the animals were decapitated and trunk blood collected. Immunoreactive CGRP was determined in plasma by radio-immuno-assay. Two groups of animals were used. The one group was vehicle treated, whereas the other group received a compound of formula I via drinking water (100 mg/l) for five days before the test.
Values for inhibition of histamine induced oedema response for some representative compounds are recorded in table 1.
The present invention also relates to pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof and, usually, such compositions also contain a pharmaceutical carrier or diluent. The compositions containing the compounds of this invention may be prepared by conventional techniques and appear in conventional forms, for example capsules, tablets, solutions or suspensions.
The pharmaceutical carrier employed may be a conventional solid or liquid carrier. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatine, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water.
Similarly, the carrier or diluent may include any time delay material known to the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
The route of administration may be any route which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary or parenteral e.g. rectal, depot, transdermal, subcutaneous, intranasal, intramuscular, topical, intravenous, intraurethral, ophthalmic solution or an ointment, the oral route being preferred.
If a solid carrier for oral administration is used, the preparation can be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
For nasal administration, the preparation may contain a compound of formula I dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application. The carrier may contain additives such as solubilising agents, e.g. propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.
For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.
A typical tablet which may be prepared by conventional tabletting techniques contains
The compounds of the invention may be administered to a mammal, especially a human, in need of such treatment, prevention, elimination, alleviation, or amelioration of an indication related to all painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role such as e.g. neurogenic pain, inflammation, migraine, neuropathy, itching and rheumatoid arthritis, as well as indications caused by or related to the secretion and circulation of insulin antagonising peptides, such as non-insulin-dependent diabetes mellitus (NIDDM) or ageing-associated obesity. Such mammals include also animals, both domestic animals, e.g. household pets, and non-domestic animals such as wildlife.
The compounds of the invention may be administered in the form of an alkali metal or earth alkali metal salt thereof, concurrently, simultaneously, or together with a pharmaceutically acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parenteral (including subcutaneous) route, in an effective amount.
For the above indications the dosage will vary depending on the compound of formula I employed, on the mode of administration and on the therapy desired. However, in general, satisfactory results are obtained with a dosage of from about 0.5 mg to about 1000 mg, preferably from about 1 mg to about 500 mg of compounds of formula I, conveniently given from 1 to 5 times daily, optionally in sustained release form. Usually, dosage forms suitable for oral administration comprise from about 0.5 mg to about 1000 mg, preferably from about 1 mg to about 500 mg of the compounds of formula I admixed with a pharmaceutical carrier or diluent.
Suitable dosage ranges varies as indicated above depending as usual upon the exact mode of administration, form in which administered, the indication towards which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.
Generally, the compounds of this invention are dispensed in unit dosage form comprising 50-200 mg of active ingredient in or together with a pharmaceutically acceptable carrier per unit dosage.
Usually, dosage forms suitable for oral, nasal, pulmonal or transdermal administration comprise from about 0.5 mg to about 1000 mg, preferably from about 1 mg to about 500 mg of the compounds of formula I admixed with a pharmaceutically acceptable carrier or diluent.
Any novel feature or combination of features described herein is considered essential to this invention.